Therapeutic method for treatment of Alzheimer&#39;s disease

ABSTRACT

A method and apparatus for treating Alzheimer&#39;s disease is disclosed. The method comprises delivering indomethacin or nonsteroidal anti-inflammatory agents having cyclooxygenase inhibitor action directly to the hippocampus or the lateral ventricle through an implanted catheter. The catheter has a flexible distal end that is implanted directly in the hippocampus or lateral ventricle as the preferred embodiment. The distal end has either a porous tip or a closed end. Where the distal end is closed, or a plurality of elution holes are present indomethacin is delivered to the hippocampus or lateral ventricle through either the porous tip or the elution holes. The catheter is part of a system for delivering indomethacin or nonsteroidal anti-inflammatory agents having cyclooxygenase inhibitor action to the hippocampus or lateral ventricle that includes a pump coupled to the catheter for delivering the indomethacin or nonsteroidal anti-inflammatory agents having cyclooxygenase inhibitor action through the catheter to the hippocampus or lateral ventricle.

This application is a division of Ser. No. 09/127,833 filed Aug. 3, 1998now U.S. Pat. No. 6,056,725 which is a division of Ser. No. 08/641,450filed Apr. 30, 1996 now U.S. Pat. No. 5,846,220.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method of treating Alzheimer's disease andmore specifically relates to delivering therapeutic nonsteroidalanti-inflammatory agents directly into the central nervous system orspecific brain structures.

2. Description of the Related Art

Studies support an inverse relationship between anti-inflammatorymedications used for treating patients with rheumatoid arthritis and anassociated low prevalence of Alzheimer's disease [J. B. Rich et.al.,Neurology 45:51-55, 1995]. Controlled studies of twin pairs havingAlzheimer's disease onset greater than 3 years provide additionalsupport that prior treatment with anti-inflammatory medications serves aprotective role in Alzheimer's disease. [J. C. S. Breitner, et.,al.,Neurology 44:227-232, 1994] Specifically, controlled double-blindedstudies have found that the anti-inflammatory agent “indomethacin”administered orally has a therapeutic benefit for mild to moderatelycognitively impaired Alzheimer's disease patients, and treatment withindomethacin during early stages of the disease has a retarding affecton disease progression compared to the placebo treated control group.[J. Rogers, et.al., Neurology 43:1609-1612. 1993] Alzheimer's patientswith moderate cognitive impairment treated with indomethacin alsoexhibit a reduction in cognitive decline. However, patients treated withoral indomethacin developed drug related adverse effects that requiredtheir treatment to be discontinued and their removal from the study.

Studies have shown indomethacin works at the cellular areas of the brainaffected by Alzheimer's disease. These cellular areas include thehippocampus, entorhinal cortex, basal forebrain, amygdala and nucleusbasalis of Meynert. In the normal brain, various enzyme systems act onamyloid precursor proteins to form peptides required for physiologicalbrain functions including cellular membrane repair.

An example of normal amyloid protein processing is the action of anendoprotease termed “alpha-secretase.” Alpha-secretase cleaves theamyloid precursor protein resulting in non-amyloidogenic peptidefragments. These non-amyloidogenic peptide fragments are required fornormal cellular function (S. B. Roberts et.al., Journal of BiologicalChemistry 269:3111-3116, 1994).

Other endoproteases, termed “beta-” and “gamma-secretases”, cleave theamyloid precursor protein to form amyloidogenic fragments capable ofinteracting with several other cellular proteins. The interaction of theamyloidogenic fragments and other cellular proteins forms enzymes thatbecome the foci of neurotoxicity and subsequently neuritic plaques ( P.Eikelenboom, et.al., TiPS 15:447-450, 1994). In particular,beta-secretase cleaves the amyloid precursor protein to form fragmentsthat result in increased calcium influx into the affected neurons. Thisincreased calcium influx affects the intracellular pH and cytokineinduction of the neurons which triggers intracellular enzymaticactivation including lipoxygenase and cyclooxygenase up-regulation.

These enzymes resulting from the interaction of the amyloidogenicfragments and other cellular proteins further disrupt intracellularmicrotubule metabolism with inhibition of protein transport blockingneurotransmission along the neurite's axon. The result of this processis senile neuritic plaque formation and neurofibrillary tanglesassociated with Alzheimer's disease.

Although the specific causes for increased cellular production ofaltered secretase activity in specific brain regions is not wellunderstood, it is known that this dysfunctional enzymatic activityresults in progressive dendritic pruning, neuronal loss and damage withmarked cognitive decrements over time.

A problem with orally administered indomethacin or other nonsteroidalanti-inflammatory drugs is unpleasant side effects including severenausea and gastric ulcers which patients develop following chronic use.Further, with chronic oral therapy the therapeutic value diminishes overtime requiring dose escalation. In addition, limited transport ofindomethacin or other nonsteroidal anti-inflammatory drugs across theblood brain barrier increases the potential for systemic adverseside-effects.

In order to maintain the same therapeutic affect with diseaseprogression, the dose of indomethacin taken orally must increase. Inpatients having adverse side-effects, treatment escalation is notpossible. Thus, oral administration of drugs such as indomethacin isinherently dose-limiting.

In addition to the problems just mentioned with orally administeredindomethacin or similar nonsteroidal anti-inflammatory drugs, the amountof drug entering the patient's blood system is minimized by uptake ofthe drugs by the gastrointestinal system.

It is therefore desirable to produce a chronic treatment regimenallowing the direct delivery of indomethacin or similar nonsteroidalanti-inflammatory drugs, having therapeutic value against the affect ofamyloidogenic protein neurotoxicity, to the desired area of the brain.Such a treatment regimen is necessary to by-pass the adverseside-effects produced by orally administered drug and subsequent drugreceptor uptake by the gastrointestinal system.

SUMMARY OF THE INVENTION

A method of treatment for Alzheimer's disease is disclosed. The methodcomprises delivering indomethacin or similar nonsteroidalanti-inflammatory drugs through an implanted catheter positioneddirectly into the hippocampus with a delivery catheter attached to adrug delivery pump containing the therapeutic drug. The catheter has aflexible distal end that is implanted directly in the hippocampus.Alternatively, the distal end of the catheter may be positioned withinthe lateral ventricles of the cerebroventricular system whichcommunicates anatomically via the inferior horn of the lateral ventricleimmediately adjacent to the hippocampus.

The distal end has either a porous tip or a closed end. Where the distalend is closed, or a plurality of elution holes are present. Indomethacinor a similar drug is delivered to the hippocampus directly or indirectlyvia the cerebroventricular system. A pump is coupled to the catheter fordelivery of the drug at a selected infusion rate. The combination of acatheter implanted directly in the brain and a pump to pump the drugthrough the catheter and out the distal end of the catheter into thebrain allows direct access across the blood brain barrier. Thus, lessdrug is required for the desired therapeutic affect compared to oral orsystemic delivery since drug is targeted within the central nervoussystem. Further, drug delivery directly to the brain limits drug accessinto the systemic circulation preventing access to secondary therapeutictargets associated with adverse side-effects associated with oral orsystemic drug delivery.

The catheter preferably comprises a first tubular portion that has agenerally cylindrical lumen of a first internal diameter and is composedof a relatively impermeable flexible material. A second tubular portionhas an open end disposed within the lumen and a closed distal enddisposed without the lumen. The second tubular portion is composed of aflexible, porous material having a preselected microporosity that isoperable to permit the therapeutic drug, for example indomethacin, toflow from the catheter into the hippocampus. The second tubular portionis selectively moveable with respect to the first tubular portion.

Alternatively, a catheter for delivering indomethacin or a similar drugto a selected site within the hippocampus comprises a tubular portioncomposed of a relatively impermeable material. The distal end of thetubular portion is closed and has one or more elution holes throughwhich indomethacin contained within the tubular portion exits thecatheter.

It is therefore an object of the invention to provide a method anddevice for treating Alzheimer's disease.

It is another object of the invention to administer indomethacin oranother similar drug more effectively to the brain.

It is another object of the invention to administer indomethacin oranother similar drug directly to the area of interest in the brain.

It is another object of the invention to administer indomethacin oranother similar drug in tightly controlled amounts to the brain.

It is another object of the invention to administer indomethacin oranother similar drug in minute dosages over time to the brain.

It is another object of the invention to continuously administerindomethacin or another similar drug over time to the brain.

It is another object of the invention to administer indomethacin oranother similar drug over time to the hippocampus in the brain.

It is another object of the invention to administer indomethacin oranother similar drug over time to the lateral ventricles in the brain.

It is another object of the invention to administer indomethacin oranother similar drug over time to the marginal aspects of the lateralventricles in the brain.

It is another object of the invention to administer indomethacin oranother similar drug to the brain directly across the blood brainbarrier.

These objects and advantages of the invention, as well as others thatwill be clear to those skilled in the art, will become apparent uponreading the following detailed description and references to thedrawings. In the drawings and throughout this disclosure, like elementswherever referred to, are referenced with like reference numbers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a saggital view of a human brain with a catheter placed sothat the distal end of the catheter is positioned in the hippocampus.

FIG. 2A is a transverse view of the human brain with the relationship ofthe hippocampus with respect to the lateral ventricle.

FIG. 2B is a coronal view of the relationship of the hippocarnpus withrespect to the inferior horn of the lateral ventricle.

FIG. 3 is a schematic depiction of the preferred embodiment of a meansfor implementing the invention with direct access into the hippocampus.

FIG. 4 is a schematic depiction of an alternate embodiment of a meansfor implementing the invention with direct access into the lateralventricle.

FIG. 5 is a schematic side view depiction of a preferred embodiment of acatheter attached to an infusion pump used in implementing the method ofthe invention.

FIG. 6 is a schematic side view depiction of an alternate embodiment ofcatheter attached to an infusion pump used in implementing the method ofthe invention.

FIG. 7 is a schematic side view depiction of a marker tip used with thecatheters of FIGS. 5 and 6.

FIG. 8 is a schematic side view depiction of a method of placing acatheter into the hippocampus.

FIG. 9 is a schematic side view depiction of a method of placing acatheter into the lateral ventricle.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the invention, indomethacin or a similar drug is delivered directlyinto a patient's hippocampus 18. Throughout this disclosure, referenceto indomethacin includes reference to drugs similar to indomethacin.Some of these drugs include therapeutic nonsteroidal anti-inflammatoryagents such as lipoxygenase or cyclooxygenase inhibitors. Suchnonsteroidal anti-inflammatory agents having cyclooxygenase inhibitoraction may include: acetaminophen, ibuprofen, fenoprofen, flurbiprofen,ketoprofen, naproxen, piroxicam, zomepirac, diclofenace, and sulindac,whereas nordihydroguaiaretic acid is a potent inhibitor of5-lipoxygenase. Also throughout this disclosure, unless statedotherwise, reference to a patient's hippocampus 18 also refers to apatient's lateral ventricle which lies immediately adjacent to thehippocampus 18.

As shown in FIG. 1, this is accomplished by implanting a catheter 10having a proximal end 12 and a distal end 14 in a patient's brain 16 sothat distal end 14 is located in the patient's hippocampus 18. FIGS. 2Aand 2B are transverse and coronal views of the human brain 16illustrating the relationship of the hippocampus 18 to the lateralventricle 11.

In the invention, proximal end 12 is attached to a source ofindomethacin. This is preferably accomplished by attaching proximal end12 to an implantable infusion pump (“IIP”) 20 through a connectingcatheter 22 having a proximal end 24 and distal end 26. Distal end 26 isattached to IIP 20 as shown in FIG. 3. Alternately, proximal end 12 maybe attached to a source of indomethacin by being connected via animplanted access port (“CAP”) 27 for percutaneous access to an externalinfusion pump 28 as shown in FIG. 3A. The combination of IIP 20 withcatheter 10 is preferred because, as will be explained hereafter, it isbelieved to be more safe for continuously infusing indomethacin to thehippocampus 18 to obtain the maximum therapeutic effect. Use of IIP 20allows indomethacin to be administered in tightly controlled, yet minutedosages over time.

In the invention alternately, indomethacin is delivered directly to apatient's lateral ventricle 11. As shown in FIG. 4, this is accomplishedby implanting a catheter 10 having a proximal end 12 and a distal end 14in a patient's brain so that the distal end 14 is located in thepatient's lateral ventricle 11.

In the invention, proximal end 12 is attached to a source ofindomethacin. This is preferably accomplished by attaching proximal end12 to an IIP 20 through a connecting catheter 22 having a proximal end24 and a distal end 26. Distal end 26 is attached to proximal end 12while proximal end 24 is attached to IIP 20. Alternately, proximal end12 may by attached to a source of indomethacin by being connected to anexternal infusion pump 28 as shown in FIG. 4A. The combination of IIP 20with catheter 10 is preferred to continuously infuse indomethacin to thelateral ventricle 11. The alternate infusion of indomethacin to thelateral ventricle 11 allows for safe access for perfusing the marginalaspect of hippocampus 18.

The detailed structure of a preferred embodiment of catheter 10 is shownin FIG. 5. Catheter 10 and distal end 14 are shown in an enlarged crosssectional view. The size of catheter 10 is not shown for simplicity ofillustration.

As has been mentioned, proximal end 12 is preferable coupled to distalend 26 of connecting catheter 22 and the proximal end 24 of connectingcatheter 22 is attached to IIP 20. The connection between proximal end12 and distal end 26 and the connection between proximal end 24 and IIP20 is shown schematically in FIG. 5. It should be understood that theactual types of connection will vary depending upon the particular typeof connecting catheter 22 and IIP 20 or CAP used as will be wellunderstood by those skilled in the art.

Catheter 10 preferably comprises an elongated tubular portion 30 havinga central lumen 32. Catheter 10 terminates at the most distal end ofdistal end 14 in tip 34. Tubular portion 30 preferably composed of amaterial that will expand in response to an external stimulus such asheat or a chemical solvent.

In one preferred embodiment, the tubular portion 30 is composed of arelatively impermeable material such as polyacrylonitrile.Polyacrylonitrile will expand in response to an external stimuli such asheat, and will return to its original shape upon cooling.

In an alternate preferred embodiment, tubular portion 30 is composed ofenhanced tear resistant silicone elastomer or polyurethane, which, whenexposed to an external stimulus such as a chemical solvent like freon,will expand. When the solvent evaporates, the silicone elastomer orpolyurethane will return to its original shape.

Whether a heat sensitive or solvent sensitive material is used, thetubular portion 30 should be biocompatible and sufficiently flexible tofacilitate insertion. A durometer shore value of 80A is preferred. Tip34 is preferably rounded to minimize tissue disruption during insertionand location of distal end 14 as will be described hereafter. Tubularportion 30 preferably has an externally tapered distal end surface 36 tominimize tissue disruption during insertion.

Catheter tip 34 has a generally tubular shape and is designed to fitsnugly within lumen 32. Catheter tip 34 has a lumen 38 to receiveindomethacin from lumen 32. Lumen 32 and the external diameter ofcatheter tip 34 should be sized so that there is a zero tolerancetherebetween. A snug fit is desirable to maintain the position ofcatheter tip 34 in relation to tubular portion 30 and to discourageseepage of indomethacin between the interface of the exterior ofcatheter tip 34 and the interior surface of tubular portion 30. However,as discussed more fully below, under certain conditions, catheter 10 maybe customized by moving catheter tip 34 in relation to tubular portion30.

Catheter tip 34 is preferable composed of a porous material such aspolysulfone hollow fiber, manufactured by Amicon, although polyethylene,polyamides, polypropylene and expanded polytetrafluoroethylene (ePTFE)are also suitable. Catheter tip 34 is preferable porous along its entirelength to enable indomethacin to flow into the hippocampus 18. Thepreferred pore size is approximately ranged between 0.1-0.2 microns.

It is preferred that the maximum pore size be less than or equal toapproximately 0.2 microns to prevent any bacterial agent that may bepresent inside catheter 10 from entering into the hippocampus 18 orlateral ventricle 11. Furthermore, at larger pore sizes, there is thepotential for tissue in-growth that may restrict the flow ofindomethacin out of catheter tip 34. By making the entire length ofcatheter tip 34 porous, a more uniform volume distribution ofindomethacin is provided. Unlike a catheter tip that has a singleelution hole or a few elution holes, catheter tip 34 in this embodimentdispenses indomethacin in a nearly 360 degree pattern along the entirelength of catheter tip 34 that is exposed to the hippocampus 18 orlateral ventricle 11.

Although the preferred embodiment of catheter tip 34 is a porous tipalong its entire length, it is also possible to have a catheter tip 34that has a single elution hole or a few elution holes along its length.Throughout this disclosure, the length of the portion of catheter tip 34that is exposed to the hippocampus 18 or lateral ventricle 11, whethercatheter tip 34 is continuously porous or has one or a few elutionholes, is represented by “x.”

As described above, tubular portion 30 is composed of a material thatwill expand in response to an external stimulus such as hear or achemical solvent. As a result, length x may be custom selected by thephysician at the time of insertion. When tubular portion 30 expands inresponse to the external stimulus, the snug fit between catheter tip 34and tubular portion 30 is relieved, and the physician may slide cathetertip 34 with respect to tubular portion 30 by hand to achieve the desiredlength x. The material from which tubular portion 30 is composed, isselected so that when the external stimulus is removed, tubular portion30 returns to its ordinary shape, thereby reestablishing the near zerotolerance fit between tubular portion 30 and catheter tip 34.

Alternately, length x may be set at the time of manufacture. Catheters10 may be manufactured having a variety of lengths x for the portion ofcatheter tip 34 that will be exposed to the hippocampus 18 or lateralventricle 11. Lengths x are preselected to produce catheters 10 forpredetermined applications in the hippocampus 18 or lateral ventricle11. These applications may be determined by the specific location in thehippocampus 18 where distal end 14 will be located and the size of thehippocampus 18 of a particular patient. Once the length x has beendetermined for a catheter 10, the length x may be established oncatheter tip 34 and catheter tip 34 may be attached to tubular portion30 as described above.

In an alternate design for catheter 10, chosen in FIG. 6, distal end 14is closed. One or a plurality of elution holes 40 extent through distalend 14 so that the indomethacin flowing through catheter 10 may exitcatheter 10 through elution holes 40. In this embodiment, the entirecatheter 10 is preferably made of a relatively impermeable material suchas polyacrylonitrile, polyethylene, polypropylene, or siliconeelastomer.

In any of the embodiments for catheter 10, distal end 14 must besufficiently pliable so that it may move to conform to the structure ofthe brain in the hippocampus 18 or lateral ventricle 11 as catheter 10is implanted in the patient as will be described hereafter. Thiscompliance may be accomplished by polymer compositions of low durometermaterials.

To practice the invention, distal end 14 is surgically implanted in thebrain 16 with distal end 14 specifically located in the patient'shippocampus 18 or lateral ventricle 11. This is preferably done byaccessing the hippocampus 18 through a posterior occipital lobe. Thisproduces the least damage to the patient's motor cortex. Similarly,accessing the lateral ventricle 11 may be performed anteriorally throughthe frontal lobe or posteriorally through the occipital lobe to preventdamaging the motor cortex and affecting the patient's motor function.Typically a trocar 42 or catheter 10 containing a stylet 44 isintroduced through the selected lobe to the patient's hippocampus 18 orlateral ventricle 11. Access and location of the trocar 42 or catheter10 containing a stylet 44 is preferably done using well known externaltriangulation techniques, stereotactic placement techniques, or magneticresonance imaging (MRI) techniques such as are commonly used, amongother things, in the placement of hydrocephalic shunts.

As shown in FIG. 8, where a trocar 42 is used to access the hippocampus18, once the trocar 42 is located in the hippocampus 18, catheter 10 ispassed through the trocar 42 so that distal end 14 leaves the trocar 42and enters the hippocampus 18. Once distal end 14 is free of the trocar42, because distal end 14 is pliable, distal end 14 will move toaccommodate the structure of the hippocampus 18. After distal end 14 islocated in the hippocampus 18, the trocar 42 is removed. Proximal end 12is attached to a source of indomethacin.

As shown in FIG. 9 where catheter 10 is located in the hippocampus 18using a stylet 44, a stylet 44 is placed in lumen 32 to add rigidity tocatheter 10. Distal end 14 is then moved to the desired location in thehippocampus 18 or lateral ventricle 11. When distal end 14 is determinedto be at the desired location in the hippocampus 18 or lateral ventricle11, the stylet is removed. When the stylet 44 is removed, because distalend 14 is pliable, distal end 14 will adapt itself to the internalstructure of either the hippocampus 18 or lateral ventricle 11. Afterthe stylet 44 is removed, proximal end 12 is attached to a source ofindomethacin.

It is preferred to place some means for locating distal end 14 duringthe access and location process. This is preferably done by applying amarker 46, as shown in FIG. 7, to distal end 14 is detected during theaccess and location process. If access and location is accomplishedusing some form of x-ray radiation, marker 46 is preferably radiopaque.Radiopaque marker 46 renders at least a portion of distal tip 14 opaqueto xrays, enabling the tip 34 to be observed via fluoroscopy or viax-ray during access and location of catheter 10.

In a preferred embodiment, the marker 46 comprises a semisphericalportion 48 that has a cylindrical nipple 50 emanating away therefrom.Hemispherical portion 48 provides a rounded profile for minimizingtissue disruption during insertion. Cylindrical nipple 50 is sized tofit snugly within the lumen 38 and is held in place via a suitablebiocompatible adhesive, such as a biocompatible medical siliconeadhesive or a medical urethane adhesive.

In a preferred embodiment, radiopaque marker 46 comprises tantalumpowder dispersed in a matrix composed of a biocompatible adhesive, suchas those discussed above. The preferred ratio of tantalum to adhesive is3 to 2. Ordinarily, radiopaque marker 46 will be premolded prior toinsertion into the lumen 38. After radiopaque marker 46 has beeninserted into the lumen 38, a thin coating of the same biocompatibleadhesive is preferably applied to the exterior of the hemisphericalportion 48. Other materials may also be suitable for radiopaque marker46. such as barium or platinum materials.

Alternately, the radiographic marker 46 may be chosen of a material thathas sufficient radiodensity for visualization during radiologicprocedures, but in powdered form that is dispersed in the catheter tip34 at the time the catheter tip 34 is molded.

Alternatively, marker 46 may be composed of a material that iscompatible to nuclear magnetic resonance imaging (MRI) to enable the tip34 to be detected during a MRI scan. Preferred material for such amarker 46 is platinum, though barium, tantalum, and similar materialsare also suitable. Regardless of whether radiography or MRI is beingutilized, the goal of providing a radiographic marker 46 is to enablethe operator to accurately detect the precise location of the tip 34 tofacilitate placement and later verification of the integrity andposition of distal end 14 of catheter 10.

After distal end 14 has been located in the hippocampus 18, proximal end12 of catheter 10 is attached to a source of indomethacin. Where thesource of indomethacin is IIP 20, proximal end 12 is attached to distalend 26 of connecting catheter 22. Connecting catheter 22 is subsequentlytunneled subcutaneously under the scalp, behind the ear and to apectoral or abdominal site where IIP 20 will be implanted. IIP 20 may beany of a number of commercially available implantable infusion pumpssuch as, for example, the SynchroMed® pump, Model 8611H, manufactured byMedtronic, Inc., Minneapolis, Minn.

Alternately, after distal end 14 has been located in the hippocampus 18or lateral ventricle 11, proximal end 12 of catheter 10 may be attachedto an external source of indomethacin. In this case, proximal end 12 isattached to an access port 52 placed in the patient's skull. Access port52 is in turn connected to a connecting catheter 54 that is attached toan external pump 28 that is connected to a reservoir of indomethacin(not shown). Pump 28 may be any of a number of commercially availableexternal infusion pumps such as, for example, Pharmacia Deltec, Inc.ambulatory infusion pumps.

Once distal end 14 has been located in the hippocampus 18 or lateralventricle 11 and proximal end 12 has been attached to either IIP 20 oran external pump 28, indomethacin is infused through catheter 10 to exitcatheter 10 distal end 14. In the embodiment of catheter 10 having aporous distal end 24. indomethacin exits catheter 10 through the porousmaterial. In the embodiment of catheter 10 having a closed distal end14, indomethacin exits catheter 10 through elution holes 40. In eitherembodiment for distal end 14, the following are believed to be desirabledosages and flow rates for the introduction of indomethacin into thehippocampus 18 ranging from 0.1-1.0 microliters per hour.

It is believed that the disclosed invention will have particulartherapeutic value if indomethacin is continually infused to thepatient's hippocampus 18. Therefore, in selecting the material forcatheter 10, care should be taken to ensure that the materials chosen iscompatible with long term exposure to indomethacin.

By practicing the disclosed invention, the unpleasant side effectsassociated with orally administering indomethacin or similar drugs areeliminated. In addition, higher concentrations of indomethacin may bepresented to the hippocampus 18 or the lateral ventricles of thecerebroventricular system than is possible with orally administeredindomethacin.

Many modifications and variations may be made in the techniques andstructures described and illustrated herein without departing from thespirit and scope of the present invention. For example, the system couldbe used to infuse a cytostatic agent into a malignant mass located inthe variety of places in the body or infuse a nerve growth factor intothe intrathecal space of the spinal column. Accordingly, the techniquesand structures described and illustrated here in should be understood tobe illustrative only and not limiting upon the scope of the presentinvention.

What is claimed is:
 1. A method of delivering indomethacin to a selectedsite within a hippocampus or latereral ventricle comprising the stepsof: a) providing a catheter having a first tubular portion that has afirst tubular portion lumen and a second tubular portion partiallydisposed within the first tubular portion lumen; b) adjusting the lengthof the second tubular portion extending from the first tubular portionlumen to conform to the dimensions of a selected site in an hippocampusor lateral ventricle; c) placing the catheter in the hippocampus orlateral ventricle so that the second tubular portion is placed at theselected site in the hippocampus or lateral ventricle; d) providing asource of indomethacin; e) coupling the catheter and the source ofindomethacin to a pump for delivering indomethacin from the source ofindomethacin to the hippocampus through the catheter; and f) actuatingthe pump to deliver the indomethacin to the hippocampus or lateralventricle.
 2. A method of delivering nonsteroidal anti-inflammatoryagents having cyclooxygenase inhibitor action to a selected site withina hippocampus or latereral ventricle comprising the steps of: a)providing a catheter having a first tubular portion that has a firsttubular portion lumen and a second tubular portion partially disposedwithin the first tubular portion lumen; b) adjusting the length of thesecond tubular portion extending from the first tubular portion lumen toconform to the dimensions of a selected site in an hippocampus orlateral ventricle; c) placing the catheter in the hippocampus or lateralventricle so that the second tubular portion is placed at the selectedsite in the hippocampus or lateral ventricle; d) providing a source ofnonsteroidal anti-inflammatory agents having cyclooxygenase inhibitoraction; e) coupling the catheter and the source of nonsteroidalanti-inflammatory agents having cyclooxygenase inhibitor action to apump for delivering nonsteroidal anti-inflammatory agents havingcyclooxygenase inhibitor action from the source of nonsteroidalanti-inflammatory agents having cyclooxygenase inhibitor action to thehippocampus through the catheter; and f) actuating the pump to deliverthe nonsteroidal anti-inflammatory agents having cyclooxygenaseinhibitor action to the hippocampus or lateral ventricle.
 3. A method oftreating Alzheimer's disease comprising the steps of: implanting thedistal end of a catheter having a distal end and a proximal end in apatient's hippocampus or lateral ventricle; attaching the proximal endof the catheter to a source of indomethacin; infusing indomethacinthrough the catheter to exit the distal end of the catheter in thepatient's hippocampus or lateral ventricle.
 4. The method of claim 3wherein the step of implanting the distal end of a catheter includes thestep of accessing the hippocampus through a posterior occipital lobe. 5.The method of claim 3 wherein the step of implanting the distal end of acatheter includes the step of anteriorally accessing the lateralventricle through the frontal lobe.
 6. The method of claim 3 wherein thestep of implanting the distal end of a catheter includes the step ofposteriorally accessing the lateral ventricle through the occipitallobe.
 7. The method of claim 3 wherein the step of implanting includesthe steps of: introducing a trocar into the patient's hippocampus orlateral ventricle; passing the catheter through the trocar so that thedistal end of the catheter leaves the trocar and enters the hippocampusor lateral ventricle; removing the trocar leaving the catheter in place.8. The method of claim 3 wherein the step of implanting includes thestep of: introducing a catheter containing a stylet through a selectedlobe to the patient's hippocampus or lateral ventricle; removing thestylet leaving the catheter in place.
 9. A method of treatingAlzheimer's disease comprising the steps of: implanting the distal endof a catheter having a distal end and a proximal end in a patient'shippocampus or lateral ventricle; attaching the proximal end of thecatheter to a source of nonsteroidal anti-inflammatory agents havingcyclooxygenase inhibitor action; infusing nonsteroidal anti-inflammatoryagents having cyclooxygenase inhibitor action through the catheter toexit the distal end of the catheter in the patient's hippocampus orlateral ventricle.